CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation

Fatemehsadat Esteghamat; James S. Broughton; Emily Smith; Rebecca Cardone; Tarun Tyagi; Mateus Guerra; András Szabó; Nelson Ugwu; Mitra V. Mani; Bani Azari; Gerald Kayingo; Sunny Chung; Mohsen Fathzadeh; Ephraim Weiss; Jeffrey Bender; Shrikant Mane; Richard P. Lifton; Adebowale Adeniran; Michael H. Nathanson; Fred S. Gorelick; John Hwa; Miklós Sahin-Tóth; Renata Belfort-DeAguiar; Richard G. Kibbey; Arya Mani

doi:10.1038/s41588-019-0470-3

CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation

Fatemehsadat Esteghamat, James S. Broughton, Emily Smith, Rebecca Cardone, Tarun Tyagi, Mateus Guerra, András Szabó, Nelson Ugwu, Mitra V. Mani, Bani Azari, Gerald Kayingo, Sunny Chung, Mohsen Fathzadeh, Ephraim Weiss, Jeffrey Bender, Shrikant Mane, Richard P. Lifton, Adebowale Adeniran, Michael H. Nathanson, Fred S. GorelickJohn Hwa, Miklós Sahin-Tóth, Renata Belfort-DeAguiar, Richard G. Kibbey, Arya Mani

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Abstract

Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.

Original language	English (US)
Pages (from-to)	1233-1243
Number of pages	11
Journal	Nature Genetics
Volume	51
Issue number	8
DOIs	https://doi.org/10.1038/s41588-019-0470-3
State	Published - Aug 1 2019
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Esteghamat, F., Broughton, J. S., Smith, E., Cardone, R., Tyagi, T., Guerra, M., Szabó, A., Ugwu, N., Mani, M. V., Azari, B., Kayingo, G., Chung, S., Fathzadeh, M., Weiss, E., Bender, J., Mane, S., Lifton, R. P., Adeniran, A., Nathanson, M. H., ... Mani, A. (2019). CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation. Nature Genetics, 51(8), 1233-1243. https://doi.org/10.1038/s41588-019-0470-3

Esteghamat, F, Broughton, JS, Smith, E, Cardone, R, Tyagi, T, Guerra, M, Szabó, A, Ugwu, N, Mani, MV, Azari, B, Kayingo, G, Chung, S, Fathzadeh, M, Weiss, E, Bender, J, Mane, S, Lifton, RP, Adeniran, A, Nathanson, MH, Gorelick, FS, Hwa, J, Sahin-Tóth, M, Belfort-DeAguiar, R, Kibbey, RG & Mani, A 2019, 'CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation', Nature Genetics, vol. 51, no. 8, pp. 1233-1243. https://doi.org/10.1038/s41588-019-0470-3

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title = "CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation",

abstract = "Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.",

author = "Fatemehsadat Esteghamat and Broughton, {James S.} and Emily Smith and Rebecca Cardone and Tarun Tyagi and Mateus Guerra and Andr{\'a}s Szab{\'o} and Nelson Ugwu and Mani, {Mitra V.} and Bani Azari and Gerald Kayingo and Sunny Chung and Mohsen Fathzadeh and Ephraim Weiss and Jeffrey Bender and Shrikant Mane and Lifton, {Richard P.} and Adebowale Adeniran and Nathanson, {Michael H.} and Gorelick, {Fred S.} and John Hwa and Mikl{\'o}s Sahin-T{\'o}th and Renata Belfort-DeAguiar and Kibbey, {Richard G.} and Arya Mani",

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AU - Esteghamat, Fatemehsadat

AU - Broughton, James S.

AU - Smith, Emily

AU - Cardone, Rebecca

AU - Tyagi, Tarun

AU - Guerra, Mateus

AU - Szabó, András

AU - Ugwu, Nelson

AU - Mani, Mitra V.

AU - Azari, Bani

AU - Kayingo, Gerald

AU - Chung, Sunny

AU - Fathzadeh, Mohsen

AU - Weiss, Ephraim

AU - Bender, Jeffrey

AU - Mane, Shrikant

AU - Lifton, Richard P.

AU - Adeniran, Adebowale

AU - Nathanson, Michael H.

AU - Gorelick, Fred S.

AU - Hwa, John

AU - Sahin-Tóth, Miklós

AU - Belfort-DeAguiar, Renata

AU - Kibbey, Richard G.

AU - Mani, Arya

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.

AB - Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.

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CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation

Abstract

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